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Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells
We previously reported pro‐survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1‐inducible signalling pathway protein‐1 (WISP‐1) consequent to β‐catenin/CREB‐dependent, TCF‐independent, signalling. However, we found that a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351844/ https://www.ncbi.nlm.nih.gov/pubmed/30548452 http://dx.doi.org/10.1111/acel.12844 |
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author | Brown, Bethan A. Connolly, Georgia M. Mill, Carina E. J. Williams, Helen Angelini, Gianni D. Johnson, Jason L. George, Sarah J. |
author_facet | Brown, Bethan A. Connolly, Georgia M. Mill, Carina E. J. Williams, Helen Angelini, Gianni D. Johnson, Jason L. George, Sarah J. |
author_sort | Brown, Bethan A. |
collection | PubMed |
description | We previously reported pro‐survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1‐inducible signalling pathway protein‐1 (WISP‐1) consequent to β‐catenin/CREB‐dependent, TCF‐independent, signalling. However, we found that as atherosclerosis advances, although Wnt5a protein was increased, WISP‐1 was reduced. We hypothesized this disconnect could be due to aging. In this study, we elucidate the mechanism underlying Wnt3a pro‐survival signalling and demonstrate the differential effect of age on Wnt3a‐ and Wnt5a‐mediated survival. We show Wnt3a protein was expressed in human atherosclerotic coronary arteries and co‐located with macrophages and VSMCs. Meanwhile, Wnt3a stimulation of primary mouse VSMCs increased β‐catenin nuclear translocation and TCF, but not CREB, activation. Wnt3a increased mRNA expression of the pro‐survival factor WISP‐2 in a TCF‐dependent manner. Functionally, β‐catenin/TCF inhibition or WISP‐2 neutralization significantly impaired Wnt3a‐mediated VSMC survival. WISP‐2 was upregulated in human atherosclerosis and partly co‐localized with Wnt3a. The pro‐survival action of Wnt3a was effective in VSMCs from young (2 month) and old (18–20 month) mice, whereas Wnt5a‐mediated rescue was impaired with age. Further investigation revealed that although Wnt5a induced β‐catenin nuclear translocation in VSMCs from both ages, CREB phosphorylation and WISP‐1 upregulation did not occur in old VSMCs. Unlike Wnt5a, pro‐survival Wnt3a signalling involves β‐catenin/TCF and WISP‐2. While Wnt3a‐mediated survival was unchanged with age, Wnt5a‐mediated survival was lost due to impaired CREB activation and WISP‐1 regulation. Greater understanding of the effect of age on Wnt signalling may identify targets to promote VSMC survival in elderly patients with atherosclerosis. |
format | Online Article Text |
id | pubmed-6351844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63518442019-02-07 Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells Brown, Bethan A. Connolly, Georgia M. Mill, Carina E. J. Williams, Helen Angelini, Gianni D. Johnson, Jason L. George, Sarah J. Aging Cell Original Papers We previously reported pro‐survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1‐inducible signalling pathway protein‐1 (WISP‐1) consequent to β‐catenin/CREB‐dependent, TCF‐independent, signalling. However, we found that as atherosclerosis advances, although Wnt5a protein was increased, WISP‐1 was reduced. We hypothesized this disconnect could be due to aging. In this study, we elucidate the mechanism underlying Wnt3a pro‐survival signalling and demonstrate the differential effect of age on Wnt3a‐ and Wnt5a‐mediated survival. We show Wnt3a protein was expressed in human atherosclerotic coronary arteries and co‐located with macrophages and VSMCs. Meanwhile, Wnt3a stimulation of primary mouse VSMCs increased β‐catenin nuclear translocation and TCF, but not CREB, activation. Wnt3a increased mRNA expression of the pro‐survival factor WISP‐2 in a TCF‐dependent manner. Functionally, β‐catenin/TCF inhibition or WISP‐2 neutralization significantly impaired Wnt3a‐mediated VSMC survival. WISP‐2 was upregulated in human atherosclerosis and partly co‐localized with Wnt3a. The pro‐survival action of Wnt3a was effective in VSMCs from young (2 month) and old (18–20 month) mice, whereas Wnt5a‐mediated rescue was impaired with age. Further investigation revealed that although Wnt5a induced β‐catenin nuclear translocation in VSMCs from both ages, CREB phosphorylation and WISP‐1 upregulation did not occur in old VSMCs. Unlike Wnt5a, pro‐survival Wnt3a signalling involves β‐catenin/TCF and WISP‐2. While Wnt3a‐mediated survival was unchanged with age, Wnt5a‐mediated survival was lost due to impaired CREB activation and WISP‐1 regulation. Greater understanding of the effect of age on Wnt signalling may identify targets to promote VSMC survival in elderly patients with atherosclerosis. John Wiley and Sons Inc. 2018-12-12 2019-02 /pmc/articles/PMC6351844/ /pubmed/30548452 http://dx.doi.org/10.1111/acel.12844 Text en © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Papers Brown, Bethan A. Connolly, Georgia M. Mill, Carina E. J. Williams, Helen Angelini, Gianni D. Johnson, Jason L. George, Sarah J. Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title | Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title_full | Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title_fullStr | Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title_full_unstemmed | Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title_short | Aging differentially modulates the Wnt pro‐survival signalling pathways in vascular smooth muscle cells |
title_sort | aging differentially modulates the wnt pro‐survival signalling pathways in vascular smooth muscle cells |
topic | Original Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351844/ https://www.ncbi.nlm.nih.gov/pubmed/30548452 http://dx.doi.org/10.1111/acel.12844 |
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